Somatostatin and somatostatin agonists for decreasing body weight

ABSTRACT

The present invention relates to a method of decreasing body weight in a patient. The method includes the step of administering a therapeutically effective amount of a somatostatin or a somatostatin agonist to said patient. A pharmaceutical/cosmetic composition comprises the somatostatin or somatostatin agonist. Such products are used to prepare such compositions for the reduction of body weight in a human or mammalian animal.

This application is a 371 of PCT/EP98/02999 filed on May 13, 1998 whichis a continuation of Ser. No. 08/854,941 filed on May 13, 1997, nowabandoned.

This invention relates to a method and composition useful for reducingbody weight in human or mammalian animal bodies.

BACKGROUND OF THE INVENTION

An estimated 35 million Americans are at least 20% overweight(Biotechnology 13:1060–1063 (1995)), a level at which health risks aresignificantly elevated. Nearly twice this number of Americans believethemselves to be overweight. A comparable picture is reported elsewhere.For example, in the United Kingdom, approximately one third of the womenand 43% of the men are overweight, with at least one in six women andone in eight men classifiable as medically obese (Purnell, S.,Highfield, The Daily Telegraph, Sep. 30, 1995). There, therefore, areboth aesthetic and health reasons for weight control.

In the medically obese population, the condition is more severe andoften associated with a myriad of serious medical problems such asnon-insulin dependent diabetes mellitus, hypertension, dyslipidemia,coronary heart disease and musculoskeletal disorders. Thus, obesity isnot just a problem of passive increase in adipose mass. It has beensuggested that the underlying metabolic alterations in obesity may beamenable to therapeutic intervention (Goldstein, D. J., et al., Am. J.Clin. Nutr., 60:647–657 (1994)).

SUMMARY OF THE INVENTION

The present invention relates to a method of decreasing body weight in apatient (e.g., a mammal such as a human). The method includes the stepof administering a therapeutically effective amount of somatostatin or asomatostatin agonist to said patient. The somatostatin or somatostatinagonist may be administered parenterally, e.g., administeredintravenously, subcutaneously, or by implantation of a sustained releaseformulation. In one embodiment, the patient is obese (e.g., as definedby either 20–25% over normal body weight (Statistical Bulletin,Metropolitan Life Insurance Co., Vol. 40, pg. 1 (1959) or as defined bybody mass index (BMI) greater than 25% over normal and including riskfactors or a BMI greater than 30% over normal (see, e.g., Bray, G A andGray, D S, Diabetes/Metabolism Review 4:653–679 (1988); Flynn, et al.,Proc. Nutritional Society 50:413 (1991)). In another embodiment, thepatient is a non-insulin dependent diabetic (i.e., type-2 diabetic).

The invention also comprises a pharmaceutical or cosmetic compositioncomprising a somatostatin or a somatostatin agonist. It furthercomprises the use of such compositions in the preparation of apharmaceutical or cosmetic composition for the reduction of excessivebody weight in a human or mammalian animal.

The term “somatostatin agonist” will be defined below. A therapeuticallyeffective amount depends upon the condition being treated, the route ofadministration chosen, and the specific activity of the compound usedand ultimately will be decided by the attending physician orveterinarian (e.g., between 5 μg/day to 5 mg/day). In one embodiment,the somatostatin agonist is administered to the patient until thepatient has lost the requisite amount of body weight (e.g., the patientis no longer medically obese). In another embodiment, the somatostatinagonist is administered for the lifetime of the patient (e.g.,maintaining normal body weight or secondary endpoints). In anotherembodiment, the somatostatin agonist is administered for cosmeticpurposes.

The somatostatin agonist may be injected parenterally, e.g.,intravenously, into the bloodstream of the subject being treated.However, it will be readily appreciated by those skilled in the art thatthe route, such as intravenous, subcutaneous, intramuscular,intraperitoneal, enterally, transdermally, transmucously, sustainedreleased polymer compositions (e.g., a lactic acid polymer or copolymermicroparticle or implant), profusion, nasal, oral, etc., will vary withthe condition being treated and the activity and bioavailability of thesomatostatin agonist being used.

While it is possible for the somatostatin agonist to be administered asthe pure or substantially pure compound, it may also be presented as apharmaceutical formulation or preparation. The formulations to be usedin the present invention, for both humans and animals, comprise any ofthe somatostatin agonists to be described below, together with one ormore pharmaceutically acceptable carriers thereof, and optionally othertherapeutic ingredients.

The carrier must be “acceptable” in the sense of being compatible withthe active ingredient(s) of the formulation (e.g., capable ofstabilizing peptides) and not deleterious to the subject to be treated.Desirably, the formulation should not include oxidizing agents or othersubstances with which peptides are known to be incompatible. Forexample, somatostatin agonists in the cyclized form (e.g., internalcysteine disulfide bond) are oxidized; thus, the presence of reducingagents as excipients could lead to an opening of the cysteine disulfidebridge. On the other hand, highly oxidative conditions can lead to theformation of cysteine sulfoxide and to the oxidation of tryptophan.Consequently, it is important to carefully select the excipient. pH isanother key factor, and it may be necessary to buffer the product underslightly acidic conditions (pH 5 to 6).

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient(s) intoassociation with the carrier which constitutes one or more accessoryingredients.

In general, the formulations for tablets or powders are prepared byuniformly and intimately blending the active ingredient with finelydivided solid carriers, and then, if necessary, as in the case oftablets, forming the product into the desired shape and size.Formulations suitable for parenteral (e.g., intravenous) administration,on the other hand, conveniently comprise sterile aqueous solutions ofthe active ingredients). Preferably, the solutions are isotonic with theblood of the subject to be treated. Such formulations may beconveniently prepared by dissolving solid active ingredient(s) in waterto produce an aqueous solution, and rendering said solution sterile. Theformulation may be presented in unit or multi-dose containers, forexample, sealed ampoules or vials.

Formulations suitable for sustained release parenteral administrations(e.g., biodegradable polymer formulations such as polyesters containinglactic or glycolic acid residues) are also well known in the art. See,e.g., U.S. Pat. Nos. 3,773,919 and 4,767,628 and PCT Publication No. WO94/15587.

The somatostatin or somatostatin agonist may also be administered withother antiobesity agents such as phentermine, diethylpropion,methamphetamine, phendimetrazine, phenmetrazine, diethylpropion,phentermine, mazindol, dextroamphetamine, phentermine, bezphetamine,orlistat, β3-adrenergic agonists (e.g., BTA-234 and SR58611A),sibutramine, henylpropanolamine, dexfenturamine, leptin, orbromocriptine.

Other features and advantages of the invention will be apparent from thefollowing description of the preferred embodiments and from the claims.

ABBREVIATIONS

-   β-Nal=β-naphthylalanine-   β-Pal=β-pyridylalanine-   hArg(Bu)=N-guanidino-(butyl)-homoarginine-   hArg(Et)₂=N,N′-guanidino-(dimethyl)-homoarginine-   hArg(CH₂CF₃)₂=N,N′-guanidino-bis-(2,2,2,-trifluoroethyl)-    homoarginine-   hArg(CH₃, hexyl)=N,N′-guanidino-(methyl, hexyl)-homoarginine-   Lys(Me)=N-methyllysine-   Lys(iPr)=N-isopropyllysine-   AmPhe=aminomethylphenylalanine-   AChxAla=aminocyclohexylalanine-   Abu=α-aminobutyric acid-   Tpo=4-thiaproline-   MeLeu=N-methylleucine-   Orn=ornithine-   Nle=norleucine-   Nva=norvaline-   Trp(Br)=5-bromo-tryptophan-   Trp(F)=5-fluoro-tryptophan-   Trp(NO₂)=5-nitro-tryptophan-   Gaba=γ-aminobutyric acid-   Bmp=β-mercaptopropionyl-   Ac=acetyl-   Pen=pencillamine

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based on the descriptionherein, utilize the present invention to its fullest extent. Thefollowing specific embodiments are, therefore, to be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference.

Somatostatin and its Agonists

Somatostatin (somatotropin release inhibiting factor or SRIF) has both a14 amino acid isoform (somatostatin-14) and a 28 amino acid isoform(somatostatin-28). See Wilson, J. & Foster, D., Williams Textbook ofEndocrinology, p. 510 (7th ed., 1985). The compound is an inhibitor ofsecretion of the growth hormone and was originally isolated from thehypothalamus. Brazeau, et al., Science 179:77 (1973). Nativesomatostatin has a very short duration of effect in vivo since it israpidly inactivated by endo- and exopeptidase. Many novel analogs havebeen prepared in order to enhance the duration of effect, biologicalactivity, and selectivity (e.g., for the particular somatostatinreceptor) of this hormone. Such analogs will be called “somatostatinagonists” herein.

Various somatostatin receptors (SSTRs) have been isolated, e.g., SSTR-1,SSTR-2, SSTR-3, SSTR-4, and SSTR-5. Thus, the somatostatin agonist maybe a SSTR-1 agonist, SSTR-2 agonist, SSTR-3 agonist, SSTR-4 agonist oran SSTR-5 agonist. In one embodiment, the somatostatin agonist of thepresent invention is an SSTR-agonist or an SSTR-2 agonist. What is meantby an “SSTR-5 agonist” or an “SSTR-2 agonist” is a compound which (1)has a high affinity (e.g., Ki of less than 1 μM or, preferably, of lessthan 10 nM, or less than 2 nM, or of less than 1 nM) for the SSTR-5 orSSTR-2, respectively (e.g., as defined by the receptor binding assaydescribed below), and (2) decreases body weight of a patient (e.g., asdefined by the biological assay described below). The somatostatinagonist may also be selective for a particular somatostatin receptor,e.g., have a higher binding affinity for a particular somatostatinreceptor subtype as compared to the other receptor subtypes. In oneembodiment, the somatostatin receptor is an SSTR-5 selective agonist orSSTR-2 selective agonist. What is meant by an SSTR-5 selective agonistis a somatostatin agonist which (1) has a higher binding affinity (i.e.,Ki) for SSTR-5 than for either SSTR-1, SSTR-2, SSTR-3, or SSTR-4 and (2)decreases body weight of a patient (e.g., as defined by the biologicalassay described below). In one embodiment, the SSTR-5 selective agonisthas a Ki for SSTR-5 that is at least 2 times (e.g., at least 5 times orat least 10 times) less than its Ki for the SSTR-2 receptor (e.g., asdefined by the receptor binding assay described below).

Somatostatin agonists which can be used to practice the therapeuticmethod of the present invention include, but are not limited to, thosecovered by formulae or those specifically recited in the publicationsset forth below, all of which are hereby incorporated by reference.

-   -   EP Application No. PS 164 EU (Inventor: G. Keri);    -   Van Binst, G. et al. Peptide Research 5:8 (1992);    -   Horvath, A. et al. Abstract, “Conformations of Somatostatin        Analogs Having Antitumor Activity”, 22nd European peptide        Symposium, Sep. 13–19, 1992, Interlaken, Switzerland;    -   PCT Application WO 91/09056 (1991);    -   EP Application 0 363 589 A2 (1990);    -   U.S. Pat. No. 4,904,642 (1990);    -   U.S. Pat. No. 4,871,717 (1989);    -   U.S. Pat. No. 4,853,371 (1989);    -   U.S. Pat. No. 4,725,577 (1988);    -   U.S. Pat. No. 4,684,620 (1987)    -   U.S. Pat. No. 4,650,787 (1987);    -   U.S. Pat. No. 4,603,120 (1986);    -   U.S. Pat. No. 4,585,755 (1986);    -   EP Application 0 203 031 A2 (1986);    -   U.S. Pat. No. 4,522,813 (1985);    -   U.S. Pat. No. 4,486,415 (1984);    -   U.S. Pat. No. 4,485,101 (1984);    -   U.S. Pat. No. 4,435,385 (1984);    -   U.S. Pat. No. 4,395,403 (1983);    -   U.S. Pat. No. 4,369,179 (1983);    -   U.S. Pat. No. 4,360,516 (1982);    -   U.S. Pat. No. 4,358,439 (1982);    -   U.S. Pat. No. 4,328,214 (1982);    -   U.S. Pat. No. 4,316,890 (1982);    -   U.S. Pat. No. 4,310,518 (1982);    -   U.S. Pat. No. 4,291,022 (1981);    -   U.S. Pat. No. 4,238,481 (1980);    -   U.S. Pat. No. 4,235,886 (1980);    -   U.S. Pat. No. 4,224,190 (1980);    -   U.S. Pat. No. 4,211,693 (1980);    -   U.S. Pat. No. 4,190,648 (1980);    -   U.S. Pat. No. 4,146,612 (1979);    -   U.S. Pat. No. 4,133,782 (1979);    -   U.S. Pat. No. 5,506,339 (1996);    -   U.S. Pat. No. 4,261,885 (1981);    -   U.S. Pat. No. 4,728,638 (1988);    -   U.S. Pat. No. 4,282,143 (1981);    -   U.S. Pat. No. 4,215,039 (1980);    -   U.S. Pat. No. 4,209,426 (1980);    -   U.S. Pat. No. 4,190,575 (1980);    -   EP Patent No. 0 389 180 (1990);    -   EP Application No. 0 505 680 (1982);    -   EP Application No. 0 083 305 (1982);    -   EP Application No. 0 030 920 (1980);    -   PCT Application No. WO 88/05052 (1988);    -   PCT Application No. WO 90/12811 (1990);    -   PCT Application No. WO 97/01579 (1997);    -   PCT Application No. WO 91/18016 (1991);    -   U.K. Application No. GB 2,095,261 (1981); and    -   French Application No. FR 2,522,655 (1983).

Examples of somatostatin agonists include, but are not limited to, thefollowing somatostatin analogs which are disclosed in the above-citedreferences:

Examples of somatostatin agonists include, but are not limited to, thefollowing somatostatin analogs which are disclosed in the above-citedreferences:

-   -   H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH₂ (BIM-23014);    -   H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-β-Nal-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-β-Nal-NH₂;    -   H-D-β-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH₂;    -   H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH;    -   H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH;    -   H-Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH;    -   H-Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH;    -   H-Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH;    -   H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol (Octreotide);    -   H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂;    -   H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂;    -   Ac-D-Phe-Lys*-Tyr-D-Trp-Lys-Val-Asp-Thr-NH₂ (an amide bridge        formed between Lys* and Asp);    -   Ac-hArg (Et)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (Et)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (Bu)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (Et)₂-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-L-hArg (Et)₂-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (CH₂CF₃)₂-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH₂;    -   Ac-D-hArg (CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHE_(t);    -   Ac-L-hArg (CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys (Me)-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys        (Me)-Thr-Cys-Thr-NHE_(t);    -   Ac-hArg (CH₃, hexyl)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   H-hArg (hexyl₂)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (Et)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHE_(t);    -   Ac-D-hArg (Et)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH₂;    -   Propionyl-D-hArg (Et)₂-Gly-Cys-Phe-D-Trp-Lys        (iPr)-Thr-Cys-Thr-NH₂;    -   Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg (Et)-NH₂;    -   Ac-D-Lys (iPr)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (CH₂CF₃)₂-D-hArg        (CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-D-hArg (CH₂CF₃)₂-D-hArg        (CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH₂;    -   Ac-D-hArg (Et)₂-D-hArg        (Et)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂;    -   Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH₂;    -   H-Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂;    -   H-Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH₂;    -   H-Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH₂;    -   H-Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Nal-NH₂;    -   H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-β-Nal-NH₂;    -   H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Lys-Val-Cys-Thr-NH₂;    -   Ac-D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH₂;    -   H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH₂;    -   H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂;    -   H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂;    -   Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂;    -   H-D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH₂;    -   H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH₂;    -   cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe);    -   cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe);    -   cyclo(Pro-Phe-D-Trp-Lys-Thr-N-Me-Phe);    -   cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe);    -   cyclo(Pro-Tyr-D-Trp-Lys-Thr-Phe);    -   cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe);    -   cyclo(Pro-Phe-L-Trp-Lys-Thr-Phe) (SEQ ID NO:1);    -   cyclo(Pro-Phe-D-Trp(F)-Lys-Thr-Phe);    -   cyclo(Pro-Phe-Trp(F)-Lys-Thr-Phe) (SEQ ID NO:2);    -   cyclo(Pro-Phe-D-Trp-Lys-Ser-Phe);    -   cyclo(Pro-Phe-D-Trp-Lys-Thr-p-C₁-Phe);    -   cyclo(D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe);    -   cyclo(D-Ala-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Phe);    -   cyclo(D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe);    -   cyclo(D-Abu-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Tyr);    -   cyclo(Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe);    -   cyclo(Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe);    -   cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe);    -   cyclo(N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe);    -   cyclo(Pro-Tyr-D-Trp-4-Amphe-Thr-Phe);    -   cyclo(Pro-Phe-D-Trp-4-Amphe-Thr-Phe);    -   cyclo(N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe);    -   cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);    -   cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba);    -   cyclo(Asn-Phe-D-Trp-Lys-Thr-Phe);    -   cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH(CH₂)₄CO);    -   cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-β-Ala);    -   cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu)-OH;    -   cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe);    -   cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gly);    -   cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);    -   cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly);    -   cyclo(Asn-Phe-Phe-D-Trp(F)-Lys-Thr-Phe-Gaba);    -   cyclo(Asn-Phe-Phe-D-Trp(NO₂)-Lys-Thr-Phe-Gaba);    -   cyclo(Asn-Phe-Phe-Trp(Br)-Lys-Thr-Phe-Gaba) (SEQ ID NO:3);    -   cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe(I)-Gaba);    -   cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr(But)-Gaba);    -   cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH;    -   cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH;    -   cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys)-OH;    -   cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu-Cys)-OH;    -   cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba);    -   cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba);    -   cyclo(Phe-Phe-D-Trp(5F)-Lys-Thr-Phe-Phe-Gaba);    -   cyclo(Asn-Phe-Phe-D-Trp-Lys(Ac)-Thr-Phe-NH—(CH₂)₃—CO);    -   cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);    -   cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);    -   cyclo(Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba);    -   H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH₂ (BIM-23268);    -   H-Cys-Phe-Phe-D-Trp-Lys-Ser-Phe-Cys-NH₂ (BIM-23284);    -   H-Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys-NH₂ (BIM-23295); and    -   H-Cys-Phe-Tyr(I)-D-Trp-Lys-Thr-Phe-Cys-NH₂ (BIM-23313).

Note that for all somatostatin agonists described herein, each aminoacid residue represents the structure of —NH—C(R)H—CO—, in which R isthe side chain (e.g., CH₃ for Ala) except for Thr-ol which means—NH—CH(CH(CH₃)OH)—CH₂—OH and Pro which means prolinyl. Lines betweenamino acid residues represent peptide bonds which join the amino acids.Also, where the amino acid residue is optically active, it is the L-formconfiguration that is intended unless D-form is expressly designated. Adisulfide bridge is formed between the two free thiols (e.g., Cys, Pen,or Bmp residues); however, it is not shown.

Use of linear somatostatin agonists of the following formula is alsowithin the invention:

wherein

-   -   A¹ is a D- or L-isomer of Ala, Leu, Ile, Val, Nle, Thr, Ser,        β-Nal, β-Pal, Trp, Phe, 2,4-dichloro-Phe, pentafluoro-Phe,        p-X-Phe, or o-X-Phe, wherein X is CH₃, Cl, Br, F, OH, OCH₃ or        NO₂;    -   A² is Ala, Leu, Ile, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp,        2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein        X is CH₃, Cl, Br, F, OH, OCH₃ or NO₂;    -   A³ is pyridyl-Ala, Trp, Phe, β-Nal, 2,4-dichloro-Phe,        pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH₃, Cl, Br,        F, OH, OCH₃ or NO₂;    -   A⁶ is Val, Ala, Leu, Ile, Nle, Thr, Abu, or Ser;    -   A⁷ is Ala, Leu, Ile, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp,        2,4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein        X is CH₃, Cl, Br, F, OH, OCH₃ or NO₂;    -   A⁸ is a D- or L-isomer of Ala, Leu, Ile, Val, Nle, Thr, Ser,        Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe,        p-X-Phe, or o-X-Phe, wherein X is CH₃, Cl, Br, F, OH, OCH₃ or        NO₂;    -   each R₁ and R₂, independently, is H, lower acyl or lower alkyl;        and R₃ is OH or NH₂; provided that at least one of A¹ and A⁸ and        one of A² and A⁷ must be an aromatic amino acid; and further        provided that A¹, A², A⁷ and A⁸ cannot all be aromatic amino        acids.

Examples of linear agonists to be used in the method of this inventioninclude:

-   -   H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH₂;    -   H-D-Phe-p-NO₂-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂;    -   H-D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂;    -   H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH₂ (BIM-23052);    -   H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂;    -   H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂; and    -   H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH₂.

If desired, one or more chemical moieties, e.g., a sugar derivative,mono or poly-hydroxy C₂₋₁₂ alkyl, mono or poly-hydroxy C₂₋₁₂ acylgroups, or a piperazine derivative, can be attached to the somatostatinagonist, e.g., to the N-terminus amino acid. See PCT Application WO88/02756, European Application 0 329 295, and PCT Application No. WO94/04752. An example of a somatostatin agonists which contain N-terminalchemical substitutions are:

Synthesis of Somatostatin Agonists

The methods for synthesizing somatostatin agonists is well documentedand are within the ability of a person of ordinary skill in the art.

Synthesis of short amino acid sequences is well established in thepeptide art. For example, synthesis ofH-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH₂, described above, can beachieved by following the protocol set forth in Example I of EuropeanPatent Application 0 395 417 A1. The synthesis of somatostatin agonistswith a substituted N-terminus can be achieved, for example, by followingthe protocol set forth in WO 88/02756, European Patent Application No. 0329 295, and PCT Publication No. WO 94/04752.

Somatostatin Receptor Binding Assays

The human SSTR-1, SSTR-2, SSTR-3, SSTR-4, and SSTR-5 cDNA clones havebeen described (SSTR-1 and SSTR-2 in Yamada, Y., et al., Proc. Natl.Acad. Sci. USA, 89:251–255 (1992); SSTR-3 in Yamada, et al., Mol.Endocrinol. 6:2136–2142 (1993); and SSTR-4 and SSTR-5 in Yamada, et al.,Biochem. Biophys. Res. Commun. 195:844–852 (1993)) and are alsoavailable from American Type Culture Collection (ATCC, Rockville, Md.)(ATCC Nos. 79044 (SSTR-1), 79046 (SSTR-2), and 79048 (SSTR-3)). Based onthe restriction endonuclease maps, the entire coding region of each SSTRcDNA may be excised by suitable restriction endonuclease digestion(Maniatis, T., et al., Molecular Cloning-A Laboratory Manual, CSHL,1982). Restriction endonucleases are available from New England Biolabs(Beverly, Mass.). This cDNA fragment was inserted into the mammalianexpression vector, pCMV (Russell, D., et al., J. Biol. Chem.,264:8222–8229 (1989)), using standard molecular biology techniques (seee.g., Maniatis, T., et al., Molecular Cloning,-A Laboratory Manual, ColdSpring Harbor Laboratory, 1982) to produce the expression plasmid,pCMV-human SSTR-1 through pCMV-human SSTR-5. Other mammalian expressionvectors include pcDNA1/Amp (Invitrogen, Sandlesy, Calif.). Theexpression plasmids were introduced into the suitable bacterial host, E.Coli HB101 (Stratagene, La Jolla, Calif.) and plasmid DNAs, fortransfection, were prepared on Cesium Chloride gradients.

CHO-K1 (ovary, Chinese hamster) cells were obtained from ATCC (ATCC No.CCL 61). The cells were grown and maintained in Ham's F12 media (GibcoBRL, Grand Island, N.Y.) supplemented with 10% fetal bovine serum understandard tissue culture conditions. For transfection, the cells wereseeded at a density 1×10⁶/60-cm plate (Baxter Scientific Products, McGawPark, Ill.). DNA mediated transfection was carried out using the calciumphosphate co-precipitation method (Ausubel, F. M., et al., CurrentProtocols in Molecular Biology, John Wiley & Sons, 1987). The plasmidpRSV-neo (ATCC; ATCC No. 37198) was included as a selectable marker at1/10 the concentration of the expression plasmid. CHO-K1 clonal celllines that have stably inherited the transfected DNA were selected forgrowth in Ham's F12 media containing 10% fetal bovine serum and 0.5mg/ml of G418 (Sigma). The cells were ring-cloned and expanded in thesame media for analysis.

Expression of the human SSTR-1 through SSTR-5 receptors in the CHO-K1cells were detected by Northern blot analysis of total RNA prepared fromthe cells (Sambrook, J. E., et al., Molecular Cloning-A LaboratoryManual, Ed. 2., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.,1989) and by receptor binding using [¹²⁵I-Tyr¹¹] somatostatin-14 as aligand. Transfected cell lines expressing the human SSTR receptors wereclonally expanded in culture and used in the following SSTR bindingprotocol.

Crude membranes were prepared by homogenization of the transfected cellsin 20 ml of ice-cold 50 mM Tris-HCl with a POLYTRON homogenizer (setting6, 15 sec). Buffer was added to obtain a final volume of 40 ml, and thehomogenate was centrifuged in a Sorval SS-34 rotor at 39,000 g for 10min at 0–4° C. The resulting supernatant was decanted and discarded. Thepellet was rehomogenized in ice-cold buffer, diluted, and centrifuged asbefore. The final pellet was resuspended in the 10 mM Tris HCl and heldon ice for the receptor binding assay.

Aliquots of the membrane preparation were incubated for 30 min at 30° C.with 0.05 nM [¹²⁵I-Tyr¹¹]somatostatin-14 (2000 Ci/mmol; Amersham Corp.,Arlington Heights, Ill.) in 50 mM HEPES (pH 7.4) containing a testsomatostatin agonist of various concentrations (e.g., 10⁻¹¹ to 10⁻⁶), 10mg/ml bovine serum albumin (fraction V) (Sigma Chemical Co., St. Louis,Mo.), MgCl₂ (5 mM), Trasylol (200 KIU ml), bacitracin (0.02 mg/ml), andphenylmethylsulphonyl fluoride (0.02 mg/ml). The final assay volume was0.3 ml. The incubations were terminated by rapid filtration through GF/Cfilters (pre-soaked in 0.3% polyethylenimine for 30 min) using a Brandelfiltration manifold. Each tube and filter were then washed three timeswith 5 ml aliquots of ice-cold buffer. Specific binding was defined asthe total [¹²⁵I-Tyr¹¹]SRIF-14 bound minus that bound in the presence of1000 nM. The Ki values for the tested somatostatin agonists werecalculated by using the following formula: Ki=IC₅₀/[1+(LC/LEC)] whereIC₅₀ is the concentration of test somatostatin agonist required toinhibit 50 percent of the specific binding of the radioligand[¹²⁵I-Tyr¹¹]somatostatin-14, LC is the concentration of the radioligand(0.05 nM), and LEC is the equilibrium dissociation constant of theradioligand (0.16 nM). The Ki values (nm) for the tested somatostatinagonists are shown in Table I.

TABLE I hSSTR-1 hSSTR-2 hSSTR-3 hSSTR-4 hSSTR-5 Somato- 2.26 0.23 1.21.8 1.41 statin-14 Somato- 2.38 0.30 1.3 7.93 0.4 statin-28 Octreotide875 0.57 26.8 5029 6.78 BIM-23014 2414 0.75 97.9 1826 5.21 BIM-2305297.6 11.96 5.6 127 1.22 BIM-23190 9120 0.35 215 7537 11.1 BIM-23197 60160.19 26.8 3897 9.81 BIM-23272 47.7 3.23 10.9 753 1.01 BIM-23284 27.919.3 35.6 58.6 0.85 BIM-23295 86.9 6.19 9.7 3.4 0.34 BIM-23313 15.1 4.7825.5 55.3 0.30 BIM-26268 1227 15.06 545 3551 0.42Weight Loss Studies

The effect of chronic (6 day) treatment with BIM-23268 on body weightgain/loss was examined in an obese animal model, the fatty: (fa/fa)Zucker rats (purchased from Harlan-Olac, Bicester, Oxon, U.K. See Bray,G., Federation Proceedings 36:148–153 (1977). Eleven male fatty Zuckerrats weighing about 450 grams were randomly divided into two groups, andtheir initial body weights recorded. The animals were housed in pairs ina normal 12 hour light:12 hour darkness cycle at 20±2° C. and fedovernight ad libitum.

For the group assigned to receive drug treatment, the rats received thetype-5 somatostatin receptor selective agonist BIM-23268C at 3 mg/kg, bysubcutaneous injection twice a day at 10:00 a.m. and 5:00 p.m. The othergroup was treated with a subcutaneous injection of 0.1 ml/100 g ofsaline twice a day at 10:00 a.m. and 5:00 p.m. The animals weresubjected to the BIM-23268 or saline treatment for a total of six days.

At 10:00 a.m. each day, food was removed and replaced with accuratelyweight 100 gram food pellet (a standard laboratory rat diet, Beekay ratand mouse diet, Bantin & Kingman, Hull, Humberside, U.K.). The amount offood remaining a 10:00 a.m. the next day was accurately weighed,recorded and replaced with 100 grams of fresh food pellets.

The animals were weighed each day during the 6-day treatment period at5:00 p.m. The untreated control group mean weight was 414.09 at thestart of the trial and was 418.89 after six days. The BIM-23268 treatedgroup's mean weight was 413.6 at the start of the trial and remained at413.6 after six days. The average food consumption for the control groupwas 26.0 g/rat/day and for the BIM-26268 group was 25.9 g/rat/day.

These results showed that body weight gain was lower in animals treatedwith BIM-23268. The effect on body weight change was not due to a toxiceffect of the agent, as the treated group appeared healthy, and therewas no difference in the amount of food consumed over the entiretreatment period.

Secondary Endpoints of Efficacy

Because of the amount of weight that must be lost to achieve aclinically important alteration in risk for various sequelae of obesity,the Food and Drug Administration guidelines for the evaluation ofweight-control drugs have recommended that additional endpoints showinga decrease in risk factors such as lipemia be monitored.

Obese (fa/fa) Zucker rats were treated as in example 1 above. On thelast day of treatment (day 6), food was removed at 5:00 p.m., and therats were fasted overnight. At 9:00 a.m. the next day, the animals weresubjected to a glucose challenge, given as 0.8 gram/kg of glucoseorally. Periodic 400 μl of blood samples were taken from the tail vein(Peterson, R. G., ILAR News, 32:16–19 (1990)) 60 min. and 30 min. beforeand at 30, 60, 90, and 120 min. after the administration of the glucosechallenge (0.8 gram/kg orally). Aprotinin (Traysylol, Bayer UK,Hayward's Health, W. Sussex, U.K. and heparin (Sigma Chemical Co.,Poole, Dorset, U.K.) were added to the blood samples to a finalconcentration of 400 KIU/ml and 100 units/ml, respectively. Plasmafractions were prepared from these samples by centrifugation at 4000×Gin a microfuge, for the estimation of triglycerides and glycerol.Samples were then stored at −80° C. until assayed.

Plasma glycerol and triglycerides were determined using the SigmaEnzymatic (Tinder) calorimetric assay kit (Cat #337-B, Sigma ChemicalCo., Poole, Dorset, U.K.) and measuring absorbance at 540 nm in aspectrophotometer.

After six days of treatment with BIM-23268C at 3 mg/kg twice a day bysubcutaneous injection, both plasma glycerol and triglycerides weresignificantly lowered, as exemplified by the samples taken at tim 30 and60 minutes before the oral glucose challenge. See FIG. 1 and FIG. 2. Theadministration of an oral glucose challenge have no significant effecton plasma lipids. The BIM-23628C treated group showed a significantlylower plasma glycerol and triglycerides throughout the 2-hour testperiod. The results suggested that BIM-23268C, following a 6-daytreatment period at the prescribed dose was effective in reducinghypertriglyceridemia.

Assessment of Efficacy in Patient

The effect of the somatostatin agonist on obesity can be examined inpatients by assessing total body weight, body mass index, total adiposetissue content, subcutaneous tissue content, visceral adipose tissuecontent (see, e.g., Zamboni, M., Amer. J. Clin. Nutr. 60:682–687 (1994).The effect of the somatostatin agonist can also be measured on othersecondary endpoints, such as insulin sensitivity (see, e.g., Bergman, R.N., et al., Endocrin. Rev. 6:45–86 (1985); Turner, R. C., Diabetes44:1–10 (1995)), blood pressure (see, e.g., Maheux, P., Hypertension24:695–698 (1994)), plasma lipids (see, e.g., Dubrey, S. W., et al.,Diabetes 43:831–835 (1994)), and the other acceptable endpointsrecommended by the FDA Draft Guidelines for the Clinical Evaluation ofWeight Control Drugs (1994) (see also, Drug & Market Development 6:36(1994)).

OTHER EMBODIMENTS

The foregoing description has been limited to specific embodiments ofthis invention. It will be apparent, however, that variations andmodifications may be made to the invention, with the attainment of someor all of the advantages of the invention. Such embodiments are alsowithin the scope of the following claims.

1. A method of decreasing body weight in a patient, wherein said patientis a non-insulin-dependent diabetic human, said method comprisingadministering a therapeutically effective amount of a somatostatintype-2 receptor agonist to said patient.
 2. The method according toclaim 1 wherein the somatostatin agonist isH-D-βNal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH₂,H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-β-Nal-NH₂,H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-β-Nal-NH₂,H-D-β-Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,H-D-Phe-Cys-Phe-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH₂,H-D-Phe-Cys-Phe-Phe-D-Trp-Lys-Thr-Pen-Thr-NH₂,H-D-Phe-Cys-Phe-Tyr-D-Trp-Lys-Thr-Pen-Thr-OH,H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-OH,H-Gly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH,H-Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH,H-Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr-OH,H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-olH-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH₂,H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,Ac-D-Phe-Lys*-Tyr-D-Trp-Lys-Val-Asp-Thr-NH₂ (an amide bridge formedbetween Lys* and Asp), Ac-hArg(Et)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂, Ac-D-hArg(Et)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,Ac-D-hArg(Bu)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂, Ac-D-hArg(Et)₂-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,Ac-L-hArg(Et)₂-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂, Ac-D-hArg(CH₂C₃)₂-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂, Ac-D-hArg(CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂, Ac-D-hArg(CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH₂,Ac-D-hArg(CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt, Ac-L-hArg(CH₂—CF₃)₂-Gy-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,Ac-D-hArg(CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NH₂,Ac-D-hArg(CH₂CF₃) 2-Gly-Cys-Phe-D-Trp-Lys(Me)-Thr-Cys-Thr-NHEt,Ac-hArg(CH₃, hexyl)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,H-hArg(hexyl₂)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,Ac-D-hArg(Et)₂-Gy-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt,Ac-D-hArg(Et)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH₂,Propionyl-D-hArg(Et)₂-Gly-Cys-Phe-D-Trp-Lys(iPr)-Thr-Cys-Thr-NH₂,Ac-D-β-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg (Et)₂—NH₂,Ac-D-Lys(iPr)-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂, Ac-D-hArg(CH₂CF₃)₂-D-hArg (CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂.Ac-D-hArg (CH₂CF₃)₂-D-hArg(CH₂CF₃)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH₂, Ac-D-hArg (Et)₂-D-hArg(Et)₂-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂,Ac-Cys-Lys-Asn-4-Cl-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH₂,H-Bmp-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,H-Bmp-Tyr-D-Trp-Lys-Val-Cys-Phe-NH₂,H-Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH₂,H-Bmp-Tyr-D-Trp-Lys-Val-Cys-S-Nal-NH₂,H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂,H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-S-Nal-NH₂,H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂,Ac-D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH₂,H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-S-Nal-NH₂,H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-S-Nal-NH₂,H-D-β-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂,H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂,Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH₂,H-D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH₂,H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH₂,cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe),cyclo(Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe),cyclo(Pro-Phe-D-Trp-Lys-Thr-N-Me-Phe),cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe), cyclo(Pro-Tyr-D-Trp-Lys-Thr-Phe),cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe), cyclo(Pro-Phe-L-Trp-Lys-Thr-Phe)(SEQID NO:1), cyclo(Pro-Phe-D-Trp(F)-Lys-Thr-Phe),cyclo(Pro-Phe-Trp(F)-Lys-Thr-Phe) (SEQ ID NO:2),cyclo(Pro-Phe-D-Trp-Lys-Ser-Phe), cyclo(Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe),cyclo(D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe),cyclo(D-Ala-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Phe),cyclo(D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe),cyclo(D-Abu-N-Me-D-Phe-D-Val-Lys-D-Trp-D-Tyr),cyclo(Pro-Tyr-D-Trp-t-4-AchxAla-Thr-Phe),cyclo(Pro-Phe-D-Trp-t-4-AchxAla-Thr-Phe),cyclo(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe),cyclo(N-Me-Ala-Tyr-D-Trp-t-4-AchxAla-Thr-Phe),cyclo(Pro-Tyr-D-Trp-4-Amphe-Thr-Phe),cyclo(Pro-Phe-D-Trp-4-Amphe-Thr-Phe),cyclo(N-Me-Ala-Tyr-D-Trp-4-Amphe-Thr-Phe),cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba),cyclo(Asn-Phe-D-Trp-Lys-Thr-Phe),cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-NH(CH₂)₄CO),cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-S-Ala),cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Glu)-OH,cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe), cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gly),cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly),cyclo(Asn-Phe-Phe-D-Trp(F)-Lys-Thr-Phe-Gaba), cyclo (Asn-Phe-Phe-D-Trp(NO₂)-Lys-Thr-Phe-Gaba), cyclo(Asn-Phe-Phe-Trp(Br)-Lys-Thr-Phe-Gaba)(SEQ ID NO:3), cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Phe(I)-Gaba),cyclo(Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr(But)-Gaba),cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH,cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys)-OH,cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Tpo-Cys)-OH,cyclo(Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-MeLeu-Cys)-OH,cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba),cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba),cyclo(Phe-Phe-D-Trp(5F)-Lys-Thr-Phe-Phe-Gaba),cyclo(Asn-Phe-Phe-D-Trp-Lys(Ac)-Thr-Phe-NH-(CH₂)₃—CO),cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),cyclo(Lys-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),cyclo(Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba),H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH₂,H-Cys-Phe-Phe-D-Trp-Lys-Ser-Phe-Cys-NH₂,H-Cys-Phe-Tyr-D-Trp-Lys-Thr-Phe-Cys-NH₂ orH-Cys-Phe-Tyr(I)-D-Trp-Lys-Thr-Phe-Cys-NH₂.
 3. The method according toclaim 1 wherein the somatostatin agonist is


4. The method according to claim 1 wherein said patient is obese.
 5. Themethod according to claim 1 wherein the somatostatin agonist is

wherein A¹ is a D- or L-isomer of Ala, Leu, Ile, Val, Nle, Thr, Ser,β-Nal, β-Pal, Trp, Phe, 2,4-dichloro-Phe, pentafluoro-Phe, p-X-Phe, oro-X-Phe, wherein X is CH₃, Cl, Br, F, OH, OCH₃ or NO₂; A² is Ala, Leu,Ile, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe,pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH₃, Cl, Br, F, OH,OCH₃ or NO₂; A³ is pyridyl-Ala, Trp, Phe, β-Nal, 2,4-dichloro-Phe,pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH₃, Cl, Br, F, OH,OCH₃ or NO₂; A⁶ is Val, Ala, Leu, Ile, Nle, Thr, Abu, or Ser; A⁷ is Ala,Leu, Ile, Val, Nle, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe,pentafluoro-Phe, o-X-Phe, or p-X-Phe, wherein X is CH₃, Cl, Br, F, OH,OCH₃ or NO₂; A⁸ is a D- or L-isomer of Ala, Leu, Ile, Val, Nle, Thr,Ser, Phe, β-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe,p-X-Phe, or o-X-Phe, wherein X is CH₃, Cl, Br, F, OH, OCH₃ or NO₂; eachR₁ and R₂, independently, is H, lower acyl or lower alkyl; and R₃ is OHor NH₂; provided that at least one of A¹ and A⁸ and one of A² and A⁷must be an aromatic amino acid; and further provided that A¹, A², A⁷ andA⁸ cannot all be aromatic amino acids.
 6. The method according to claim5 wherein the linear somatostatin agonist isH-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH₂,H-D-Phe-p-NO₂-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂,H-D-Nal-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂,H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH₂,H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂,H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂ orH-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-β-D-Nal-NH₂.